CN108379260A - A kind of purposes of 1,3- Ben Bing Evil mercaptan -2- ketone compounds in preparing monoamine oxidase inhibitors - Google Patents

A kind of purposes of 1,3- Ben Bing Evil mercaptan -2- ketone compounds in preparing monoamine oxidase inhibitors Download PDF

Info

Publication number
CN108379260A
CN108379260A CN201810102771.XA CN201810102771A CN108379260A CN 108379260 A CN108379260 A CN 108379260A CN 201810102771 A CN201810102771 A CN 201810102771A CN 108379260 A CN108379260 A CN 108379260A
Authority
CN
China
Prior art keywords
monoamine oxidase
purposes
ketone compounds
ben bing
oxidase inhibitors
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201810102771.XA
Other languages
Chinese (zh)
Other versions
CN108379260B (en
Inventor
孔德信
王栋
左之利
王雅琪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huazhong Agricultural University
Original Assignee
Huazhong Agricultural University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Huazhong Agricultural University filed Critical Huazhong Agricultural University
Priority to CN201810102771.XA priority Critical patent/CN108379260B/en
Publication of CN108379260A publication Critical patent/CN108379260A/en
Application granted granted Critical
Publication of CN108379260B publication Critical patent/CN108379260B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/39—Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses structures 1 as shown in formula (I), purposes of 3 Ben Bing Evil mercaptan, 2 ketone compounds in preparing monoamine oxidase inhibitors, it is tested by vitro enzyme activity experiment, such compound has good inhibitory activity to monoamine oxidase A and B, and reference and inspiration new approaches are provided to develop novel MAO inhibitor.

Description

A kind of 1,3- Ben Bing Evil mercaptan -2- ketone compounds inhibit preparing monoamine oxidase Purposes in agent
Technical field
The invention belongs to pharmaceutical technology field, the pharmacy for being related to one kind 1,3- Ben Bing Evil mercaptan -2- ketone compounds is newly used On the way, the new application especially in preparing monoamine oxidase inhibitors.
Background technology
Monoamine neurotransmitter includes norepinephrine, adrenaline, dopamine and serotonin, is in neurotransmitter Most important one kind.The expression of these neurotransmitters and its metabolite and many diseases are closely related, affect the mankind Attention, emotion and behavior.For example, the reduction of 5-HT concentration can cause depression in human body；Dopamine is dense in nervous system The reduction of degree can induce parkinsonism and Alzheimer's disease.The degradation adjusting of these monoamine neurotransmitters mainly passes through Monoamine oxidase (monoamine oxidase, MAO) is completed, and therefore, inhibits the activity of MAO that can improve monoamine god Expression through mediator and the generation for reducing harmful amine metabolite.It can be seen that MAO is a kind of important drug discovery Target.
Monoamine oxidase is a kind of important oxidoreducing enzyme.There are two kinds of MAO hypotypes, MAO-A and MAO-B in human body. Similitude with height between the two hypotypes.But they have the selectivity of substrate larger difference.MAO-A is usually urged Change serotonin, norepinephrine, adrenaline.Then the neurotransmitters such as P-Toluidine, phenyl ethylamine have height to MAO-B hypotypes Affinity.Since the selectivity of their substrates is different, clinically the inhibitor for treating of the two hypotypes is used not at present Same disease.Such as MAO-A inhibitor is mainly used for treating depression, social phobia, pain, migraine；And MAO-B inhibits Agent is mainly used for treating Alzheimer's disease and parkinsonism.
Invention content
The object of the present invention is to provide a kind of 1,3- Ben Bing Evil mercaptan -2- ketone compounds to prepare monoamine oxidase inhibition Application in agent.
In order to realize the above-mentioned purpose of the present invention, present invention employs following technical solutions：
The structural formula of the 1,3- Ben Bing Evil mercaptan -2- ketone compounds is as follows：
Wherein, R1 is one of H or following groups：
R2 be H or
What is listed in table 1 is three particular compounds.
1 classes of compounds of table and its substituent group
Present invention firstly discovers that and by active testing, demonstrating iso-indoles -1,3- cyclohexadione compounds shown in formula (I) With monoamine oxidase A, B inhibitory activity, provide new application of such compound as monoamine oxidase inhibitors, be expected to by Develop into the medicine of the diseases such as depression, social phobia, pain, migraine, Alzheimer's disease, parkinsonism Object.
Specific implementation mode
Below by embodiment the present invention is described in detail, but the present invention is not limited with this.In embodiment The compound used is purchased from Dutch specs companies (http://www.specs.com), it is specs companies chemical combination Compound in object library.
Embodiment 1：The compounds of this invention is to the active test of monoamine oxidase inhibitors
1. experiment reagent
The compounds of this invention, MAOA (Active Motif, Cat.No.31502), MAOB (Active Motif, Cat.No.31503), clorgiline Clorgyline (Sigma, Cat.No.M3778), Si Liji orchids R (-)-deprenyl (Abcam, Cat.No.ab120604), 384 orifice plates (from Perkin Elmer, Cat.No.6007299)
2. experimental method
1) the compounds of this invention is dissolved to 100mM with 100% DMSO, HEPES bit buffering liquid is added in porous plate, Compound is transferred in porous plate, the concentration of DMSO is made to be reduced to 1%.
2) enzyme and substrate are dissolved into respectively in buffer solution, move into the substrate solution of 10 μ L, start reaction, stand 60 points Clock, is added the fluorescein of 20 μ L, and mixing stands 20 minutes at room temperature, measures and record the relative luminance of fluorescence signal, exist respectively Percent inhibition of the compound to enzyme is measured under 10 concentration conditions.
3) it is control with clorgiline, Si Liji orchids in testing, experiment repeats 2-3 times, calculates separately maximum fluorescence value and most Small fluorescent value and its standard deviation calculate the reliability of each group of porous version data with the ratio between maximum fluorescence value and minimum fluorescent value.
3. data processing
1) Excel is used to calculate the inhibiting rate of each compound according to that formula one
Inh%=(Max-Signal)/(Max-Min) * 100 Equation (1)
2) use GraphPad Prism5 by the percent inhibition of each compound enzyme of gained under 10 concentration conditions It is fitted according to formula two, calculates the IC50 values of compound, Y and X is percent inhibition and compound concentration respectively in formula.
Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * Hill Slope)) Equation (2)
4. experimental result
The compounds of this invention is screened through monoamine oxidase inhibitory activity, and measures corresponding half effective inhibition concentration (IC50).The chemical constitution of 3 1,3- Ben Bing Evil mercaptan -2- ketone compounds selected from formula (I) and its to monoamine oxidase Inhibiting rate and IC50 activity are as shown in the table.
Inhibitory activity of 2 compound of table to monoamine oxidase
No. MAOA% A_IC50/μM MAOB% B_IC50/μM
1 42 8.5 97 0.027
2 68 5 21 >50
3 92 1.3 77 4.2
Compound provided by the invention is can be seen that from upper table result, and good inhibition is shown to MAO-A and MAO-B Activity.

Claims (1)

1. 1,3- Ben Bing Evil mercaptan -2- ketone compounds are in preparing monoamine oxidase inhibitors shown in structure such as formula (I) Purposes,
Wherein, R1 is one of H or following groups：
R2 be H or
CN201810102771.XA 2018-02-01 2018-02-01 Application of 1, 3-benzoxathiol-2-ketone compound in preparation of monoamine oxidase inhibitor Expired - Fee Related CN108379260B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810102771.XA CN108379260B (en) 2018-02-01 2018-02-01 Application of 1, 3-benzoxathiol-2-ketone compound in preparation of monoamine oxidase inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810102771.XA CN108379260B (en) 2018-02-01 2018-02-01 Application of 1, 3-benzoxathiol-2-ketone compound in preparation of monoamine oxidase inhibitor

Publications (2)

Publication Number Publication Date
CN108379260A true CN108379260A (en) 2018-08-10
CN108379260B CN108379260B (en) 2021-02-19

Family

ID=63074961

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810102771.XA Expired - Fee Related CN108379260B (en) 2018-02-01 2018-02-01 Application of 1, 3-benzoxathiol-2-ketone compound in preparation of monoamine oxidase inhibitor

Country Status (1)

Country Link
CN (1) CN108379260B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008052078A2 (en) * 2006-10-24 2008-05-02 Wyeth Benzoxathiine and benzoxathiole derivatives and uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008052078A2 (en) * 2006-10-24 2008-05-02 Wyeth Benzoxathiine and benzoxathiole derivatives and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARMELA GNERRE ET AL.: "Inhibition of Monoamine Oxidases by Functionalized Coumarin Derivatives: Biological Activities, QSARs, and 3D-QSARs", 《J. MED. CHEM.》 *
SAMANTHA MOSTERT ET AL.: "Inhibition of monoamine oxidase by benzoxathiolone analogues", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

Also Published As

Publication number Publication date
CN108379260B (en) 2021-02-19

Similar Documents

Publication Publication Date Title
Dixon et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death
Tsimbouri et al. Nanotopographical effects on mesenchymal stem cell morphology and phenotype
Caragher et al. Monoamines in glioblastoma: complex biology with therapeutic potential
Petroulakis et al. mTOR signaling: implications for cancer and anticancer therapy
Kaminska et al. MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target
Gaestel et al. Protein kinases as small molecule inhibitor targets in inflammation
Egusa et al. The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells
Pambid et al. Overcoming resistance to Sonic Hedgehog inhibition by targeting p90 ribosomal S6 kinase in pediatric medulloblastoma
Abbosh et al. GalR2/3 mediates proliferative and trophic effects of galanin on postnatal hippocampal precursors
Suzuki et al. Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide
Jia et al. MicroRNA‐338‐3p inhibits tumor growth and metastasis in osteosarcoma cells by targeting RUNX2/CDK4 and inhibition of MAPK pathway
Maciagiewicz et al. Structure–activity studies of RNA-binding oxazolidinone derivatives
Hwang et al. Chemicals that modulate stem cell differentiation
Hu et al. A biomimetic gelatin-based platform elicits a pro-differentiation effect on podocytes through mechanotransduction
Maayah et al. 5-, 12-and 15-Hydroxyeicosatetraenoic acids induce cellular hypertrophy in the human ventricular cardiomyocyte, RL-14 cell line, through MAPK-and NF-κB-dependent mechanism
Maayah et al. Development of cellular hypertrophy by 8-hydroxyeicosatetraenoic acid in the human ventricular cardiomyocyte, RL-14 cell line, is implicated by MAPK and NF-κB
Hwang et al. Nanotopological plate stimulates osteogenic differentiation through TAZ activation
Lei et al. Overcoming multidrug resistance by knockout of ABCB1 gene using CRISPR/Cas9 system in SW620/Ad300 colorectal cancer cells
Yu et al. In PC3 prostate cancer cells ephrin receptors crosstalk to β1-integrins to strengthen adhesion to collagen type I
Wang et al. Inverse expression levels of EphrinA3 and EphrinA5 contribute to dopaminergic differentiation of human SH-SY5Y cells
Rebuzzini et al. Arsenic trioxide alters the differentiation of mouse embryonic stem cell into cardiomyocytes
Batohi et al. Citral and its derivatives inhibit quorum sensing and biofilm formation in Chromobacterium violaceum
Xi et al. Cytotoxicity and altered c‐myc gene expression by medical polyacrylamide hydrogel
Tohtong et al. Dependence of metastatic cancer cell invasion on MLCK-catalyzed phosphorylation of myosin regulatory light chain
Zhang et al. Intestinal stem cells–types and markers

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20210219

Termination date: 20220201